Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested ...in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.
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•Anti-cancer drugs have variable efficacy within patient populations•Drug combinations give each patient more chances that one drug could be effective•Clinical efficacy of many combinations is accurately predicted without drug synergy•Optimizing drug independence represents a new way to design cancer treatments
Patient-to-patient variability in response to single drugs is sufficient to explain the efficacy of a large number of combination cancer therapies without pharmacologically additive or synergistic effect in individual patients.
Background & Aims Well established risk factors for intrahepatic cholangiocarcinoma such as biliary tract inflammation and liver flukes are not present in most Western countries patients. Although ...cirrhosis and other causes of chronic liver disease have been implicated, their contribution as risk factors for cholangiocarcinoma is unclear and our aims were to analyze these emerging potential risk factors by systematic examination of case–control series from geographically diverse regions. Methods We performed a literature review and meta-analysis of case–control studies on intrahepatic cholangiocarcinoma and cirrhosis and related risk factors. Tests of heterogeneity, publication bias and sensitivity analyses were performed and an overall odds ratio and 95% confidence intervals calculated. Results Eleven studies from both high and low prevalence regions were identified. All studies except those evaluating cirrhosis, diabetes, and obesity exhibited significant heterogeneity. Cirrhosis was associated with a combined OR of 22.92 (95% CI = 18.24–28.79). Meta-analysis estimated the overall odds ratio (with 95% confidence intervals) for defined risk factors such as hepatitis B: 5.10 (2.91–8.95), hepatitis C: 4.84 (2.41–9.71), obesity: 1.56 (1.26–1.94), diabetes mellitus type II: 1.89 (1.74–2.07), smoking: 1.31 (0.95–1.82), and alcohol use: 2.81 (1.52–5.21). Sensitivity analysis did not alter the odds ratio for any risk factors except smoking and there was no evidence of publication bias. Conclusions Cirrhosis, chronic hepatitis B and C, alcohol use, diabetes, and obesity are major risk factors for intrahepatic cholangiocarcinoma. These data suggest a common pathogenesis of primary intrahepatic epithelial cancers.
Organic materials naturally lend themselves to the crafting of structure and function using the strategies of self-assembly and supramolecular chemistry employed so effectively by biological systems. ...This perspective illustrates progress over the past two decades on self-assembly in materials chemistry through research on systems where function is directly linked to noncovalent interactions among molecules. The genesis of this approach in chemistry of materials involves the design of relatively simple structures using hydrogen bonding, π–π stacking, metal–ligand interactions, electrostatic forces, strong dipole–dipole association, hydrophobic forces, and steric repulsion. Gradually many new and exciting opportunities have emerged, such as supramolecular nanostructures that assemble into functional bulk materials and supramolecular polymers in which the motif of covalent connections among monomers is imitated by creating one-dimensional assemblies of an arbitrarily large set of molecules in both composition and size. Supramolecular polymers offer the opportunity to create structures that integrate unprecedented order in 1D assemblies with interesting dynamics through bond reversibility. Other fascinating systems are those in which intermolecular interactions and other forces can be used to create the hierarchical and highly functional structures ubiquitous in biology, such as bone and muscle, in which different types of order exist within the same structure at different length scales. Directions that have a bright future include nonequilibrium dynamic materials with the capacity to be adaptive, self-repairing, chemically alterable, and even replicativeall characteristics we see in living organic matter. Additional promising areas include 2D and 3D systems that are not necessarily classical crystals and the rational synthesis of functional organic–inorganic hybrid materials. The most exciting aspect of self-assembly and supramolecular chemistry is their open ended nature, and these are two areas of chemistry for which many new principles will be established in this century.
New biological models are incorporating the realistic processes underlying biological responses to climate change and other human-caused disturbances. However, these more realistic models require ...detailed information, which is lacking for most species on Earth. Current monitoring efforts mainly document changes in biodiversity, rather than collecting the mechanistic data needed to predict future changes. We describe and prioritize the biological information needed to inform more realistic projections of species' responses to climate change. We also highlight how trait-based approaches and adaptive modeling can leverage sparse data to make broader predictions. We outline a global effort to collect the data necessary to better understand, anticipate, and reduce the damaging effects of climate change on biodiversity.
The evolution of antibiotic resistance can now be rapidly tracked with high-throughput technologies for bacterial genotyping and phenotyping. Combined with new approaches to evolve resistance in the ...laboratory and to characterize clinically evolved resistant pathogens, these methods are revealing the molecular basis and rate of evolution of antibiotic resistance under treatment regimens of single drugs or drug combinations. In this Progress article, we review these new tools for studying the evolution of antibiotic resistance and discuss how the genomic and evolutionary insights they provide could transform the diagnosis, treatment and predictability of antibiotic resistance in bacterial infections.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
There is an increasing need to construct engineering structures in the Arctic seas. The requirement is principally generated by the oil and gas industry, because of the substantial reserves that are ...known to exist offshore in the Beaufort Sea, the Caspian Sea, the Barents Sea, the Pacific Ocean off the coast of Sakhalin, the Canadian Arctic, and almost certainly elsewhere. Structures have to withstand the severe environmental forces generated by sea ice, a subject that is developing rapidly but is still far from completely understood. Underwater pipelines have to be safe against ice gouging and strudel scour, but also have to be constructed safely and economically. The social and human environment has to be understood and respected.
Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs ...that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.
Each successive generation of X-ray machines has opened up new frontiers in science, such as the first radiographs and the determination of the structure of DNA. State-of-the-art X-ray sources can ...now produce coherent high-brightness X-rays of greater than kiloelectronvolt energy and promise a new revolution in imaging complex systems on nanometre and femtosecond scales. Despite the demand, only a few dedicated synchrotron facilities exist worldwide, in part because of the size and cost of conventional (accelerator) technology. Here we demonstrate the use of a new generation of laser-driven plasma accelerators, which accelerate high-charge electron beams to high energy in short distances, to produce directional, spatially coherent, intrinsically ultrafast beams of hard X-rays. This reduces the size of the synchrotron source from the tens of metres to the centimetre scale, simultaneously accelerating and wiggling the electron beam. The resulting X-ray source is 1,000 times brighter than previously reported plasma wigglers and thus has the potential to facilitate a myriad of uses across the whole spectrum of light-source applications.
Covalent and supramolecular polymers are two distinct forms of soft matter, composed of long chains of covalently and noncovalently linked structural units, respectively. We report a hybrid system ...formed by simultaneous covalent and supramolecular polymerizations of monomers. The process yields cylindrical fibers of uniform diameter that contain covalent and supramolecular compartments, a morphology not observed when the two polymers are formed independently. The covalent polymer has a rigid aromatic imine backbone with helicoidal conformation, and its alkylated peptide side chains are structurally identical to the monomer molecules of supramolecular polymers. In the hybrid system, covalent chains grow to higher average molar mass relative to chains formed via the same polymerization in the absence of a supramolecular compartment. The supramolecular compartments can be reversibly removed and re-formed to reconstitute the hybrid structure, suggesting soft materials with novel delivery or repair functions.
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